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- Title
Lasting s-ketamine block of spreading depolarizations in subarachnoid hemorrhage: a retrospective cohort study.
- Authors
Santos, Edgar; Olivares-Rivera, Arturo; Major, Sebastian; Sánchez-Porras, Renán; Uhlmann, Lorenz; Kunzmann, Kevin; Zerelles, Roland; Kentar, Modar; Kola, Vasilis; Aguilera, Adrian Hernández; Herrera, Mildred Gutierrez; Lemale, Coline L.; Woitzik, Johannes; Hartings, Jed A.; Sakowitz, Oliver W.; Unterberg, Andreas W.; Dreier, Jens P.
- Abstract
<bold>Objective: </bold>Spreading depolarizations (SD) are characterized by breakdown of transmembrane ion gradients and excitotoxicity. Experimentally, N-methyl-D-aspartate receptor (NMDAR) antagonists block a majority of SDs. In many hospitals, the NMDAR antagonist s-ketamine and the GABAA agonist midazolam represent the current second-line combination treatment to sedate patients with devastating cerebral injuries. A pressing clinical question is whether this option should become first-line in sedation-requiring individuals in whom SDs are detected, yet the s-ketamine dose necessary to adequately inhibit SDs is unknown. Moreover, use-dependent tolerance could be a problem for SD inhibition in the clinic.<bold>Methods: </bold>We performed a retrospective cohort study of 66 patients with aneurysmal subarachnoid hemorrhage (aSAH) from a prospectively collected database. Thirty-three of 66 patients received s-ketamine during electrocorticographic neuromonitoring of SDs in neurointensive care. The decision to give s-ketamine was dependent on the need for stronger sedation, so it was expected that patients receiving s-ketamine would have a worse clinical outcome.<bold>Results: </bold>S-ketamine application started 4.2 ± 3.5 days after aSAH. The mean dose was 2.8 ± 1.4 mg/kg body weight (BW)/h and thus higher than the dose recommended for sedation. First, patients were divided according to whether they received s-ketamine at any time or not. No significant difference in SD counts was found between groups (negative binomial model using the SD count per patient as outcome variable, p = 0.288). This most likely resulted from the fact that 368 SDs had already occurred in the s-ketamine group before s-ketamine was given. However, in patients receiving s-ketamine, we found a significant decrease in SD incidence when s-ketamine was started (Poisson model with a random intercept for patient, coefficient - 1.83 (95% confidence intervals - 2.17; - 1.50), p < 0.001; logistic regression model, odds ratio (OR) 0.13 (0.08; 0.19), p < 0.001). Thereafter, data was further divided into low-dose (0.1-2.0 mg/kg BW/h) and high-dose (2.1-7.0 mg/kg/h) segments. High-dose s-ketamine resulted in further significant decrease in SD incidence (Poisson model, - 1.10 (- 1.71; - 0.49), p < 0.001; logistic regression model, OR 0.33 (0.17; 0.63), p < 0.001). There was little evidence of SD tolerance to long-term s-ketamine sedation through 5 days.<bold>Conclusions: </bold>These results provide a foundation for a multicenter, neuromonitoring-guided, proof-of-concept trial of ketamine and midazolam as a first-line sedative regime.
- Publication
Critical Care, 2019, Vol 23, Issue 1, p1
- ISSN
1364-8535
- Publication type
journal article
- DOI
10.1186/s13054-019-2711-3